PT1362855E - Compostos de beta-lactama, processo para a sua preparação eagentes de diminuição do colesterol sérico que os contêm - Google Patents

Compostos de beta-lactama, processo para a sua preparação eagentes de diminuição do colesterol sérico que os contêm Download PDF

Info

Publication number: PT1362855E
Authority: PT; Portugal
Prior art keywords: compound; compounds; group; general formula; fluorophenyl
Prior art date: 2001-02-23

Application number

PT02703861T

Other languages

English (en)

Portuguese (pt)

Inventor

Hiroshi Tomiyama

Masayuki Yokota

Atsushi Noda

Akira Ohno

Original Assignee

Kotobuki Pharmaceutical Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2001-02-23

Filing date

2002-02-20

Publication date

2007-12-04

2002-02-20 Application filed by Kotobuki Pharmaceutical Co Ltd filed Critical Kotobuki Pharmaceutical Co Ltd

2007-12-04 Publication of PT1362855E publication Critical patent/PT1362855E/pt

Links

238000000034 method Methods 0.000 title claims description 67
239000003529 anticholesteremic agent Substances 0.000 title claims description 13
210000002966 serum Anatomy 0.000 title claims description 12
-1 Beta-lactam compounds Chemical class 0.000 title description 60
230000008569 process Effects 0.000 title description 3
229940127226 anticholesterol agent Drugs 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 383
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 23
150000003839 salts Chemical class 0.000 claims abstract description 16
125000000217 alkyl group Chemical group 0.000 claims abstract description 8
125000005843 halogen group Chemical group 0.000 claims abstract description 7
125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 3
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract 2
238000005859 coupling reaction Methods 0.000 claims description 8
150000003952 β-lactams Chemical class 0.000 claims description 8
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
239000003781 beta lactamase inhibitor Substances 0.000 claims description 3
229940126813 beta-lactamase inhibitor Drugs 0.000 claims description 3
238000003800 Staudinger reaction Methods 0.000 claims description 2
125000003118 aryl group Chemical group 0.000 claims description 2
101100058670 Aeromonas hydrophila subsp. hydrophila (strain ATCC 7966 / DSM 30187 / BCRC 13018 / CCUG 14551 / JCM 1027 / KCTC 2358 / NCIMB 9240 / NCTC 8049) bsr gene Proteins 0.000 claims 1
238000006683 Mannich reaction Methods 0.000 claims 1
125000004429 atom Chemical group 0.000 claims 1
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 1
125000005243 carbonyl alkyl group Chemical group 0.000 abstract description 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
239000000203 mixture Substances 0.000 description 89
239000000243 solution Substances 0.000 description 66
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 54
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 46
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
230000015572 biosynthetic process Effects 0.000 description 41
238000003786 synthesis reaction Methods 0.000 description 40
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
238000006243 chemical reaction Methods 0.000 description 33
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 32
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
238000005160 1H NMR spectroscopy Methods 0.000 description 29
238000010898 silica gel chromatography Methods 0.000 description 29
239000012267 brine Substances 0.000 description 27
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
239000012044 organic layer Substances 0.000 description 20
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 17
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
210000000813 small intestine Anatomy 0.000 description 15
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 14
230000009467 reduction Effects 0.000 description 14
238000006722 reduction reaction Methods 0.000 description 14
239000011734 sodium Substances 0.000 description 13
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
FXLVHFGMKHRPIU-UHFFFAOYSA-N 2-(oxan-3-yl)acetic acid Chemical compound OC(=O)CC1CCCOC1 FXLVHFGMKHRPIU-UHFFFAOYSA-N 0.000 description 10
239000003054 catalyst Substances 0.000 description 10
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
239000011541 reaction mixture Substances 0.000 description 10
150000004795 grignard reagents Chemical class 0.000 description 9
230000000871 hypocholesterolemic effect Effects 0.000 description 9
239000002904 solvent Substances 0.000 description 9
238000003756 stirring Methods 0.000 description 9
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 8
238000005984 hydrogenation reaction Methods 0.000 description 8
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
230000000694 effects Effects 0.000 description 7
239000002024 ethyl acetate extract Substances 0.000 description 7
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 7
239000010410 layer Substances 0.000 description 7
239000007858 starting material Substances 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
229930182476 C-glycoside Natural products 0.000 description 6
150000000700 C-glycosides Chemical group 0.000 description 6
239000007818 Grignard reagent Substances 0.000 description 6
239000002841 Lewis acid Substances 0.000 description 6
235000012000 cholesterol Nutrition 0.000 description 6
150000007517 lewis acids Chemical class 0.000 description 6
239000000725 suspension Substances 0.000 description 6
FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 5
102000005744 Glycoside Hydrolases Human genes 0.000 description 5
108010031186 Glycoside Hydrolases Proteins 0.000 description 5
239000002253 acid Substances 0.000 description 5
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
239000003153 chemical reaction reagent Substances 0.000 description 5
238000001816 cooling Methods 0.000 description 5
238000010511 deprotection reaction Methods 0.000 description 5
239000000706 filtrate Substances 0.000 description 5
150000002303 glucose derivatives Chemical class 0.000 description 5
238000010930 lactamization Methods 0.000 description 5
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 5
238000002360 preparation method Methods 0.000 description 5
VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 5
238000000746 purification Methods 0.000 description 5
238000007363 ring formation reaction Methods 0.000 description 5
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
QTVIACZCHBLVMC-UHFFFAOYSA-N 1-(4-fluorophenyl)azetidin-2-one Chemical compound C1=CC(F)=CC=C1N1C(=O)CC1 QTVIACZCHBLVMC-UHFFFAOYSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
238000005481 NMR spectroscopy Methods 0.000 description 4
238000006069 Suzuki reaction reaction Methods 0.000 description 4
229940125782 compound 2 Drugs 0.000 description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
238000005858 glycosidation reaction Methods 0.000 description 4
230000007062 hydrolysis Effects 0.000 description 4
238000006460 hydrolysis reaction Methods 0.000 description 4
150000002466 imines Chemical class 0.000 description 4
239000000463 material Substances 0.000 description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
229910000104 sodium hydride Inorganic materials 0.000 description 4
239000000758 substrate Substances 0.000 description 4
238000012360 testing method Methods 0.000 description 4
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
238000007341 Heck reaction Methods 0.000 description 3
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
238000010521 absorption reaction Methods 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
239000000872 buffer Substances 0.000 description 3
230000003197 catalytic effect Effects 0.000 description 3
230000001906 cholesterol absorption Effects 0.000 description 3
239000013078 crystal Substances 0.000 description 3
235000005911 diet Nutrition 0.000 description 3
230000037213 diet Effects 0.000 description 3
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
239000003112 inhibitor Substances 0.000 description 3
238000004519 manufacturing process Methods 0.000 description 3
JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 3
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230000003647 oxidation Effects 0.000 description 3
238000007254 oxidation reaction Methods 0.000 description 3
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
230000003389 potentiating effect Effects 0.000 description 3
229920006395 saturated elastomer Polymers 0.000 description 3
239000007787 solid Substances 0.000 description 3
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 3
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 3
AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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102000004190 Enzymes Human genes 0.000 description 2
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JJNHBFYGCSOONU-UHFFFAOYSA-M carbanide;cyclopenta-1,3-diene;dimethylaluminum;titanium(4+);chloride Chemical compound [CH3-].[Ti+3]Cl.C[Al]C.C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 JJNHBFYGCSOONU-UHFFFAOYSA-M 0.000 description 1
229910002091 carbon monoxide Inorganic materials 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
230000008859 change Effects 0.000 description 1
239000003638 chemical reducing agent Substances 0.000 description 1
239000002026 chloroform extract Substances 0.000 description 1
HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
229960003324 clavulanic acid Drugs 0.000 description 1
238000002648 combination therapy Methods 0.000 description 1
229940126214 compound 3 Drugs 0.000 description 1
229940127573 compound 38 Drugs 0.000 description 1
229910000365 copper sulfate Inorganic materials 0.000 description 1
ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
239000002285 corn oil Substances 0.000 description 1
235000005687 corn oil Nutrition 0.000 description 1
239000012043 crude product Substances 0.000 description 1
238000006264 debenzylation reaction Methods 0.000 description 1
238000005828 desilylation reaction Methods 0.000 description 1
FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 description 1
238000005906 dihydroxylation reaction Methods 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical group CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 1
239000003814 drug Substances 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
230000002526 effect on cardiovascular system Effects 0.000 description 1
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
230000002255 enzymatic effect Effects 0.000 description 1
238000006911 enzymatic reaction Methods 0.000 description 1
230000032050 esterification Effects 0.000 description 1
ZRSDQBKGDNPFLT-UHFFFAOYSA-N ethanol;oxolane Chemical compound CCO.C1CCOC1 ZRSDQBKGDNPFLT-UHFFFAOYSA-N 0.000 description 1
IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical group CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
239000008103 glucose Substances 0.000 description 1
229950002441 glucurolactone Drugs 0.000 description 1
229940097042 glucuronate Drugs 0.000 description 1
229940097043 glucuronic acid Drugs 0.000 description 1
230000023611 glucuronidation Effects 0.000 description 1
239000008187 granular material Substances 0.000 description 1
238000011905 homologation Methods 0.000 description 1
238000007327 hydrogenolysis reaction Methods 0.000 description 1
230000000260 hypercholesteremic effect Effects 0.000 description 1
239000005457 ice water Substances 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
239000003446 ligand Substances 0.000 description 1
150000002632 lipids Chemical class 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
UKZCGMDMXDLAGZ-UHFFFAOYSA-M magnesium;2-methylpropane;bromide Chemical compound [Mg+2].[Br-].C[C-](C)C UKZCGMDMXDLAGZ-UHFFFAOYSA-M 0.000 description 1
CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
230000004060 metabolic process Effects 0.000 description 1
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
JCAZSWWHFJVFPP-UHFFFAOYSA-N methyl 5-chloro-5-oxopentanoate Chemical compound COC(=O)CCCC(Cl)=O JCAZSWWHFJVFPP-UHFFFAOYSA-N 0.000 description 1
125000004492 methyl ester group Chemical group 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
229940099246 mevacor Drugs 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
239000011707 mineral Substances 0.000 description 1
238000002156 mixing Methods 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 description 1
ONDXXAPHPJPFKQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphoryl]-n-methylmethanamine;oxolane Chemical compound C1CCOC1.CN(C)P(=O)(N(C)C)N(C)C ONDXXAPHPJPFKQ-UHFFFAOYSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
230000004903 negative regulation of intestinal cholesterol absorption Effects 0.000 description 1
229910052759 nickel Inorganic materials 0.000 description 1
235000021590 normal diet Nutrition 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
235000016709 nutrition Nutrition 0.000 description 1
230000035764 nutrition Effects 0.000 description 1
PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
125000002524 organometallic group Chemical group 0.000 description 1
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
159000000001 potassium salts Chemical class 0.000 description 1
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
239000000843 powder Substances 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
230000008707 rearrangement Effects 0.000 description 1
238000010992 reflux Methods 0.000 description 1
238000011160 research Methods 0.000 description 1
238000012552 review Methods 0.000 description 1
229930182490 saponin Natural products 0.000 description 1
150000007949 saponins Chemical class 0.000 description 1
235000017709 saponins Nutrition 0.000 description 1
238000000926 separation method Methods 0.000 description 1
QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
238000013112 stability test Methods 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
239000000829 suppository Substances 0.000 description 1
229920002994 synthetic fiber Polymers 0.000 description 1
239000003826 tablet Substances 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
239000010936 titanium Substances 0.000 description 1
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
229910052723 transition metal Inorganic materials 0.000 description 1
150000003624 transition metals Chemical class 0.000 description 1
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
Diabetes (AREA)
Hematology (AREA)
Obesity (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Engineering & Computer Science (AREA)
Life Sciences & Earth Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Steroid Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Plural Heterocyclic Compounds (AREA)
Cephalosporin Compounds (AREA)
Hydrogenated Pyridines (AREA)

PT02703861T 2001-02-23 2002-02-20 Compostos de beta-lactama, processo para a sua preparação eagentes de diminuição do colesterol sérico que os contêm PT1362855E (pt)

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Application Number	Priority Date	Filing Date	Title
JP2001048202		2001-02-23
JP2001128031		2001-04-25

Publications (1)

Publication Number	Publication Date
PT1362855E true PT1362855E (pt)	2007-12-04

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PT02703861T PT1362855E (pt)	2001-02-23	2002-02-20	Compostos de beta-lactama, processo para a sua preparação eagentes de diminuição do colesterol sérico que os contêm

Country Status (17)

Country	Link
US (1)	US7045515B2 (ja)
EP (1)	EP1362855B1 (ja)
JP (1)	JP4229701B2 (ja)
KR (1)	KR100721639B1 (ja)
CN (1)	CN1273467C (ja)
AT (1)	ATE374769T1 (ja)
AU (1)	AU2002237522B2 (ja)
BR (1)	BRPI0206193B1 (ja)
CA (1)	CA2438961C (ja)
DE (1)	DE60222742T2 (ja)
DK (1)	DK1362855T3 (ja)
ES (1)	ES2294101T3 (ja)
MX (1)	MXPA03005073A (ja)
PT (1)	PT1362855E (ja)
RU (1)	RU2301799C2 (ja)
TW (1)	TWI291957B (ja)
WO (1)	WO2002066464A1 (ja)

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NZ569814A (en) *	2006-01-18	2011-10-28	Schering Corp	Cannibinoid receptor modulators
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JP2010500300A (ja)	2006-08-08	2010-01-07	サノフィ−アベンティス	アリールアミノアリール−アルキル−置換イミダゾリジン−２，４−ジオン、それらの製造法、それらの化合物を含有する薬剤、およびそれらの使用
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CN101541795A (zh)	2006-09-15	2009-09-23	先灵公司	用于治疗疼痛、糖尿病和脂类代谢紊乱的螺-稠合氮杂环丁烷衍生物
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2002
- 2002-02-08 TW TW091102310A patent/TWI291957B/zh not_active IP Right Cessation
- 2002-02-20 EP EP02703861A patent/EP1362855B1/en not_active Expired - Lifetime
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Also Published As

Publication number	Publication date
DE60222742T2 (de)	2008-07-17
BRPI0206193B1 (pt)	2016-05-24
CA2438961C (en)	2010-02-16
TWI291957B (en)	2008-01-01
US20040063929A1 (en)	2004-04-01
JP4229701B2 (ja)	2009-02-25
KR20030076690A (ko)	2003-09-26
DK1362855T3 (da)	2008-01-28
EP1362855A4 (en)	2005-02-23
MXPA03005073A (es)	2003-09-05
ATE374769T1 (de)	2007-10-15
WO2002066464A1 (fr)	2002-08-29
EP1362855A1 (en)	2003-11-19
CN1492865A (zh)	2004-04-28
AU2002237522B2 (en)	2007-08-02
EP1362855B1 (en)	2007-10-03
CN1273467C (zh)	2006-09-06
HK1060357A1 (en)	2004-08-06
US7045515B2 (en)	2006-05-16
JPWO2002066464A1 (ja)	2004-06-17
RU2003128424A (ru)	2005-01-27
KR100721639B1 (ko)	2007-05-23
DE60222742D1 (de)	2007-11-15
BR0206193A (pt)	2004-02-03
RU2301799C2 (ru)	2007-06-27
CA2438961A1 (en)	2002-08-29
ES2294101T3 (es)	2008-04-01

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